RESUMO
Parental behavior is essential for mammalian offspring to survive. Because of this significance, elucidating the neurobiological mechanisms that facilitate parental behavior has received strong interest. Decades of studies utilizing pharmacology and molecular biology have revealed that in addition to its facilitatory effects on parturition and lactation, oxytocin (OT) promotes the expression of parental behavior in rodents. Recent studies have also described the modulation of sensory processing by OT and the interaction of the OT system with other brain regions associated with parental behavior. However, the precise neurobiological mechanisms underlying the facilitation of caregiving behaviors by OT remain unclear. In this Review, I summarize the findings from rats and mice with a view toward integrating past and recent progress. I then review recent advances in the understanding of the molecular, cellular, and circuit mechanisms of OT-mediated parental behavior. Based on these observations, I propose a hypothetical model that would explain the mechanisms underlying OT-mediated parental behavior. Finally, I conclude by discussing some major remaining questions and propose potential future research directions.
RESUMO
In recent decades, human fathers across the globe have shown a substantial increase in their engagement in paternal caregiving behaviors. Despite the growing interest, the precise neurobiological mechanisms underlying caregiving behaviors in males remain unclear. Neurobiological studies conducted on rodents have advanced our understanding of the molecular, cellular, and circuit-level mechanisms. Typically, sexually naïve males exhibit aggression toward offspring, while fathers display parental behaviors. This drastic behavioral plasticity may be associated with changes in connections among specific regions or cell types. Recent studies have begun to describe this structural plasticity by comparing neural connections before and after fatherhood. In this Perspective, we summarize the findings from four well-studied rodent species, namely prairie voles, California mice, laboratory rats, and laboratory mice, with a view toward integrating past and current progress. We then review recent advances in the understanding of structural plasticity for parental behaviors. Finally, we discuss remaining questions that require further exploration to gain a deeper understanding of the neural mechanisms underlying paternal behaviors in males, including their possible implications for the human brain.
Assuntos
Encéfalo , Roedores , Animais , Masculino , Humanos , Encéfalo/metabolismo , Comportamento Paterno , Neurônios/metabolismo , Arvicolinae , PaisRESUMO
The hormone oxytocin, secreted from oxytocin neurons in the paraventricular (PVH) and supraoptic (SO) hypothalamic nuclei, promotes parturition, milk ejection, and maternal caregiving behaviors. Previous experiments with whole-body oxytocin knockout mice showed that milk ejection was the unequivocal function of oxytocin, whereas parturition and maternal behaviors were less dependent on oxytocin. Whole-body knockout, however, could induce the enhancement of expression of related gene(s), a phenomenon called genetic compensation, which may hide the actual functions of oxytocin. In addition, the relative contributions of oxytocin neurons in the PVH and SO have not been well documented. Here, we show that females with conditional knockout of oxytocin gene in both the PVH and SO undergo grossly normal parturition and maternal caregiving behaviors, while dams with a smaller number of remaining oxytocin-expressing neurons exhibit severe impairments in breastfeeding, leading to the death of their pups within 24 hours after birth. We also found that the growth of pups is normal even under oxytocin conditional knockout in PVH and SO as long as pups survive the next day of delivery, suggesting that the reduced oxytocin release affects the onset of lactation most severely. These phenotypes are largely recapitulated by SO-specific oxytocin conditional knockout, indicating the unequivocal role of oxytocin neurons in the SO in successful breastfeeding. Given that oxytocin neurons not only secrete oxytocin but also non-oxytocin neurotransmitters or neuropeptides, we further performed cell ablation of oxytocin neurons in the PVH and SO. We found that cell ablation of oxytocin neurons leads to no additional abnormalities over the oxytocin conditional knockout, suggesting that non-oxytocin ligands expressed by oxytocin neurons have negligible functions on the responses measured in this study. Collectively, our findings confirm the dispensability of oxytocin for parturition or maternal behaviors, as well as the importance of SO-derived oxytocin for breastfeeding.
Assuntos
Ocitocina , Núcleo Supraóptico , Feminino , Camundongos , Animais , Ocitocina/farmacologia , Núcleo Supraóptico/metabolismo , Neurônios/metabolismo , Hipotálamo/metabolismo , Lactação/fisiologia , Núcleo Hipotalâmico Paraventricular/metabolismoRESUMO
Decades of studies have revealed molecular and neural circuit bases for body weight homeostasis. Neural hormone oxytocin (Oxt) has received attention in this context because it is produced by neurons in the paraventricular hypothalamic nucleus (PVH), a known output center of hypothalamic regulation of appetite. Oxt has an anorexigenic effect, as shown in human studies, and can mediate satiety signals in rodents. However, the function of Oxt signaling in the physiological regulation of appetite has remained in question, because whole-body knockout (KO) of Oxt or Oxt receptor (Oxtr) has little effect on food intake. We herein show that acute conditional KO (cKO) of Oxt selectively in the adult PVH, but not in the supraoptic nucleus, markedly increases body weight and food intake, with an elevated level of plasma triglyceride and leptin. Intraperitoneal administration of Oxt rescues the hyperphagic phenotype of the PVH Oxt cKO model. Furthermore, we show that cKO of Oxtr selectively in the posterior hypothalamic regions, especially the arcuate hypothalamic nucleus, a primary center for appetite regulations, phenocopies hyperphagic obesity. Collectively, these data reveal that Oxt signaling in the arcuate nucleus suppresses excessive food intake.
Assuntos
Leptina , Ocitocina , Humanos , Camundongos , Animais , Hiperfagia , Obesidade/genética , Núcleo Hipotalâmico Paraventricular , Peso Corporal , Hipotálamo , Hipotálamo Posterior , TriglicerídeosRESUMO
The adult brain can flexibly adapt behaviors to specific life-stage demands. For example, while sexually naive male mice are aggressive to the conspecific young, they start to provide caregiving to infants around the time when their own young are expected. How such behavioral plasticity is implemented at the level of neural connections remains poorly understood. Here, using viral-genetic approaches, we establish hypothalamic oxytocin neurons as the key regulators of the parental caregiving behaviors of male mice. We then use rabies-virus-mediated unbiased screening to identify excitatory neural connections originating from the lateral hypothalamus to the oxytocin neurons to be drastically strengthened when male mice become fathers. These connections are functionally relevant, as their activation suppresses pup-directed aggression in virgin males. These results demonstrate the life-stage associated, long-distance, and cell-type-specific plasticity of neural connections in the hypothalamus, the brain region that is classically assumed to be hard-wired.
Assuntos
Agressão , Ocitocina , Agressão/fisiologia , Animais , Humanos , Hipotálamo/fisiologia , Masculino , Camundongos , Neurônios/fisiologia , PaisRESUMO
Precocious movements are widely seen in embryos of various animal species. Whether such movements via proprioceptive feedback play instructive roles in motor development or are a mere reflection of activities in immature motor circuits is a long-standing question. Here we image the emerging motor activities in Drosophila embryos that lack proprioceptive feedback and show that proprioceptive experience is essential for the development of locomotor central pattern generators (CPGs). Downstream of proprioceptive inputs, we identify a pioneer premotor circuit composed of two pairs of segmental interneurons, whose gap-junctional transmission requires proprioceptive experience and plays a crucial role in CPG formation. The circuit autonomously generates rhythmic plateau potentials via IP3-mediated Ca2+ release from internal stores, which contribute to muscle contractions and hence produce proprioceptive feedback. Our findings demonstrate the importance of self-generated movements in instructing motor development and identify the cells, circuit, and physiology at the core of this proprioceptive feedback.
Assuntos
Drosophila , Retroalimentação Sensorial , Animais , Junções Comunicantes , Interneurônios , Movimento/fisiologiaRESUMO
How cell-type-specific physiological properties shape neuronal functions in a circuit remains poorly understood. We addressed this issue in the Drosophila mushroom body (MB), a higher olfactory circuit, where neurons belonging to distinct glomeruli in the antennal lobe feed excitation to three types of intrinsic neurons, α/ß, α'/ß', and γ Kenyon cells (KCs). Two-photon optogenetics and intracellular recording revealed that whereas glomerular inputs add similarly in all KCs, spikes were generated most readily in α'/ß' KCs. This cell type was also the most competent in recruiting GABAergic inhibition fed back by anterior paired lateral neuron, which responded to odors either locally within a lobe or globally across all lobes depending on the strength of stimuli. Notably, as predicted from these physiological properties, α'/ß' KCs had the highest odor detection speed, sensitivity, and discriminability. This enhanced discrimination required proper GABAergic inhibition. These results link cell-type-specific mechanisms and functions in the MB circuit.
Assuntos
Cálcio/metabolismo , Corpos Pedunculados/fisiologia , Neurônios/fisiologia , Bulbo Olfatório/fisiologia , Olfato , Animais , Drosophila melanogaster/fisiologia , Neuroimagem/métodos , Técnicas de Patch-Clamp/métodos , Sinapses/metabolismoRESUMO
Halorhodopsin (NpHR), a light-driven microbial chloride pump, enables silencing of neuronal function with superb temporal and spatial resolution. Here, we generated a transgenic line of Drosophila that drives expression of NpHR under control of the Gal4/UAS system. Then, we used it to dissect the functional properties of neural circuits that regulate larval peristalsis, a continuous wave of muscular contraction from posterior to anterior segments. We first demonstrate the effectiveness of NpHR by showing that global and continuous NpHR-mediated optical inhibition of motor neurons or sensory feedback neurons induce the same behavioral responses in crawling larvae to those elicited when the function of these neurons are inhibited by Shibire(ts), namely complete paralyses or slowed locomotion, respectively. We then applied transient and/or focused light stimuli to inhibit the activity of motor neurons in a more temporally and spatially restricted manner and studied the effects of the optical inhibition on peristalsis. When a brief light stimulus (1-10 sec) was applied to a crawling larva, the wave of muscular contraction stopped transiently but resumed from the halted position when the light was turned off. Similarly, when a focused light stimulus was applied to inhibit motor neurons in one or a few segments which were about to be activated in a dissected larva undergoing fictive locomotion, the propagation of muscular constriction paused during the light stimulus but resumed from the halted position when the inhibition (>5 sec) was removed. These results suggest that (1) Firing of motor neurons at the forefront of the wave is required for the wave to proceed to more anterior segments, and (2) The information about the phase of the wave, namely which segment is active at a given time, can be memorized in the neural circuits for several seconds.